Recent studies aimed at understanding the cellular events responsible for the neuropathological features of AD have focused on the contribution of the 39-43 residue amyloid Beta-peptide, Abeta, Abeta deposits which accumulate in normal human brain as a function of aging are found in greater abundance in the brains of patients with AD. The elevated generation of Abeta resulting from proteolysis of the amyloid precursor protein (APP) as a consequence of mutations in all three early onset familial AD genes ultimately leads to a higher burden of Abeta-amyloid plaques. Furthermore, Down's syndrome (trisomy21) patients who possess three copies of the APP gene often develop symptoms of AD in later years. The enzymes responsible for APP metabolism most importantly the Beta- and Gamma-secretases responsible for generating Abeta, have not been identified. However, based on the analysis of AP fragments accumulating in the presence of protease inhibitors, generation of the N-terminus of Abeta can be blocked by a serine protease inhibitor while the gamma-secretase particularly for the production of Abeta40 is blocked by a cysteine protease inhibitor. Using the interaction trap screen we identified a putative novel human serine protease (NHSP) that binds the cysteine-rich region of the APP ectodomain. This protease is a member of the htrA class of serine protease which is highly conserved throughout evolution. Members of this family or protease have a signal peptide sequence and are induced by stress. This study is aimed at obtaining sufficient cellular data to determine whether this interaction significantly impacts APP metabolism. Towards this end, we will assay for the binding of NHSP to APP with standard biochemical techniques, identify the subcellular compartment in which NHSP resides, and test for the potential consequences of increased or decreased NHSP activity on APP processing, especially with regard to its ability to function as a alpha- or Beta-secretase.